Reduction of Uric Acid to Prevent Hypertension (RAPHY Trial) (Abstract) Hypertension affects one-third of the US population and is the major cause of cardiovascular disease. An elevated uric acid consistently predicts the development of hypertension and is commonly present in new onset hypertension. We found that nearly 90% of new onset hypertension in adolescents is associated with a high uric acid. In a recent double blind study we found that BP became normal in 86% of such adolescents when serum uric acid was lowered to <5 mg/dl (vs 3% of placebo-treated subjects). Raising uric acid in animals also causes hypertension which is mediated by activation of the renin-angiotensin system, inhibition of endothelial function (lowering nitric oxide), and the development of vascular disease in the kidneys. Furthermore, both clinical and experimental studies also suggest lowering uric acid may have other benefits, including improvement in endothelial function and a reduction in the development of metabolic syndrome and diabetes. Our preliminary data suggest that uric acid mediated hypertension develops in a two step fashion, first by reversible vasoconstriction mediated by the renin-angiotensin system and reduction of endothelial NO, the second by irreversible alteration of renal afferent arterioles leading to a permanent sodium dependent hypertension. These data suggest that there may be a window of opportunity for the prevention of hypertension in the young. Consequently, we propose a 15-center clinical trial to test the hypotheses that lowering uric acid will reduce the progressive rise in blood pressure and decrease the incidence of insulin resistance. Power analysis indicates that we will need 400 prehypertensive (by JNC7 criteria for adults and 4th Task Force criteria for adolescents) subjects age 12-50 with elevated uric acid levels (>6.0 mg/dl) to detect a 5 mmHg difference in systolic or diastolic BP between treated and control subjects after 1 year of treatment and after 2 years of post treatment follow up. The primary endpoints will be change in systolic and diastolic blood pressure and prevalence of insulin resistance at 12 and 36 months. The combined adolescent and young adult trial will determine the utility of hypouricemic therapy and the age range during which the therapy is effective. If the hypothesis is correct, this study will provide a novel and effective way to reduce the epidemic of hypertension, obesity and cardiovascular disease that current grips the world's population. PUBLIC HEALTH RELEVANCE: Planning Grant: Project Narrative Our preliminary studies in both animal models and human clinical trials suggest that elevated serum uric acid may be causally involved in the development of essential hypertension in adolescents. We propose a multi-center clinical trial to determine if reduction of serum uric acid will prevent the progressive rise in blood pressure in those at highest risk for development of hypertension, patients with pre-hypertension. This trial may provide a new paradigm for preventive therapy of hypertension, a disease that effecting more than 30% of Americans and causes nearly 1 million deaths a year in the USA.